The studies constitute an extension of our investigation of the pathophysiology of clinical disorders of renal acidification. Studies have been designed to investigate the role of chronic hyperkalemia in the pathogenesis of metabolic acidosis in patients with renal insufficiency, with special reference to the effects of chronic hyperkalemia on renal hydrogen ion secretion and ammonium production and net acid excretion. In patients with chronic renal insufficiency complicated by hyperkalemic acidosis, studies are designed to investigate the efficacy of furosemide and thiazide diuretics in ameliorating acidosis and hyperkalemia, with special reference to the effects of these agents on renal acid-base physiology; to investigate the efficacy of furosemide and thiazide therapy as alternatives to fludrocortisone therapy in correcting acidosis in a subgroup of patients with aldosterone deficiency (secondary to impaired renal secretion) in whom the salt-retaining effects of mineralocorticoid are deleterious; to investigate the combined effects of furosemide and fludrocortisone administration on systemic and renal acid-base hemeostasis, with respect to the possibility that the natriuretic effect of furosemide will offset the undesired antinatriuretic effect of fludrocortisone and amplify the desired acid-excretory and kaliuretic effect of fludrocortisone. Additional studies are in progress to determine physiological requirements and amplifiers of the renal acidosis-producing effect of aldosterone deficiency, with special reference to the effects of hyperkalemia and sodium depletion, conditions which occur as consequences of aldosterone deficiency. Further studies have been designed to investigate whether the reduction in circulating aldosterone known to occur in response to depletion of body potassium is a homeostatic component of the defense against systemic alkalosis which accompanies potassium depletion, and to determine whether the efficience of renal conservation of potassium is promoted by hypoaldosteronemia. In infants and children presenting with renal hyperchloremic acidosis associated with persistent hyperkalemia (so-called type 4 RTA), studies have been designed to investigate the physiological character and natural history of the acidification dysfunction.